HIF-2Α Promotes Osteoarthritis Progression by Regulating Articular Cartilage Deg-eneration Through Activation of CXCR4

Peng XU; Yazhou XIAO; Zhengliang LEI; Huan LIU; Luchang LIU

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Peng XU, Yazhou XIAO, Zhengliang LEI, Huan LIU, Luchang LIU. HIF-2Α Promotes Osteoarthritis Progression by Regulating Articular Cartilage Deg-eneration Through Activation of CXCR4[J]. Journal of Kunming Medical University.

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HIF-2Α Promotes Osteoarthritis Progression by Regulating Articular Cartilage Deg-eneration Through Activation of CXCR4

1.
Orthopedic Center
2.
Hand and Foot Microsurgery
3.
Oral Center，Yibin Second People’s Hospital/West China Hospital of Sichuan University Yibin Hospital，Yibin Sichuan 644000，China

Received Date: 2025-07-25

Abstract

Abstract

Objective To investigate the specific molecular mechanisms by which the hypoxia-inducible factor 2alpha （HIF-2α）/C-X-C chemokine receptor 4 （CXCR4） pathway regulates the progression of osteoarthritis （OA）. Method A cartilage degeneration cell model was established using primary chondrocytes from male C57BL/6 mice. Co-transfected cells with pcDNA, pcDNA-HIF-2α, si-NC, si-HIF-2α, and si-CXCR4 plasmids. Detected expression levels of HIF-2α, CXCR4, MMP-3, Collagen II, and aggrecan via RT-qPCR, Western blot, and immunofluorescence. Flow cytometry assessed apoptosis, while ELISA measured levels of inflammatory mediators PGE₂, IL-6, IL-1β, and TNF-α. EMSA, ChIP, and dual luciferase assays validated the interaction between HIF-2α and CXCR4. Results HIF-2α promoted chondrocyte apoptosis under hypoxic conditions by upregulating MMP-3 expression and secretion of inflammatory mediators PGE2, IL-6, IL-1β, and TNF-α （P < 0.05） while downregulating Collagen II and aggrecan expression （P < 0.001）. HIF-2α binds to the CXCR4 promoter to regulate its transcriptional expression. HIF-2α promotes OA progression under hypoxia by activating CXCR4. Knockdown of CXCR4 inhibited HIF-2α's promotion of chondrocyte inflammation, degradation, and apoptosis, thereby alleviating OA progression. Conclusion The HIF-2α/CXCR4 axis effectively mediates chondrocyte inflammation, matrix degradation, and apoptosis.

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References(35)

References

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